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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 19424

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Special Issue Editors

Dr. Diego García-Ayuso

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Guest Editor

1. Department of Ophthalmology, Optometry, Ears Nose and Throat, and Pathology, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain
2. Biosanitary Research Institute of Murcia-Virgen de la Arrixaca (IMIB-Arrixaca), C/ Campo, 12, El Palmar, 30120 Murcia, Spain
Interests: retina; retinal degeneration; retinal diseases; retinal ganglion cells; eyes; photoreceptor cells; eye diseases; taurine; contact lenses; dry eye; myopia control; optometry
Special Issues, Collections and Topics in MDPI journals

Dr. Johnny Di Pierdomenico

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Guest Editor

Department of Ophthalmology, Optometry, Ears Nose and Throat, and Pathology, Faculty of Medicine, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Virgen de la Arrixaca), University of Murcia, 30120 Murcia, Spain
Interests: retinitis pigmentosa; retinal remodeling; glaucoma; phototoxicity microglia; Müller cells; bone-marrow-derived stem cells; stem cells, neurotrophic factors: cones; retinal ganglion cells; melanopsin; contact lenses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The retina is part of the central nervous system with unique advantages for studying neurodegeneration and neuroprotection. Because of its location within the eye, it is easily accessible for local small-dose therapies. In addition, the efficacy of the treatments can be evaluated in vivo using morphological (e.g., optical coherence tomography, OCT) and functional tests (e.g., electroretinography, ERG).

The leading causes of irreversible blindness in the world are at present photoreceptor degenerative diseases in their many forms (inherited, acquired or induced) and glaucoma. Most clinically identifiable diseases cause blindness through neuronal degeneration of photoreceptors and/or retinal pigment epithelial cells or retinal ganglion cells (RGCs) in the case of retinal degenerative diseases affecting the outer or inner retina, respectively. These diseases are in many cases heterogeneous and multifactorial, which complicates the identification of effective treatment, currently non-existent, and therefore represent a major burden on the health system, due to the increase in life expectancy, and also on the economy, as they often affect working-age adults. In addition, it is now widely recognized that photoreceptor degenerations cause, over time, retinal disorganization and complete retinal remodeling, culminating in the degeneration and death of RGCs, the afferent neurons of the retina, which further complicates the success of many of the therapies proposed for these diseases. In addition to retinal neuronal death, it is worth noting the role of retinal glia in the course of these diseases and, in particular, in retinal remodeling and glial seal formation.

This Special Issue aims to study retinal degenerative diseases to shed light on the events that take place in the retina during the course of these diseases, such as neuronal degeneration, glial activation, etc., as well as their possible present and future treatments.

Dr. Diego García-Ayuso
Dr. Johnny Di Pierdomenico
Guest Editors

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Keywords

retina
photoreceptor degenerative diseases
inherited retinal degenerations
glaucoma
retinal pigment epithelial cells
retinal ganglion cells (RGCs)
neuronal degeneration
glial activation

Published Papers (9 papers)

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Research

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21 pages, 3780 KiB

Open AccessArticle

Evaluation of Photobiomodulation and Boldine as Alternative Treatment Options in Two Diabetic Retinopathy Models

by Víctor Calbiague García, Bárbara Cadiz, Pablo Herrera, Alejandra Díaz and Oliver Schmachtenberg

Int. J. Mol. Sci. 2023, 24(9), 7918; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097918 - 27 Apr 2023

Cited by 4 | Viewed by 1540

Abstract

Diabetic retinopathy causes progressive and irreversible damage to the retina through activation of inflammatory processes, overproduction of oxidative species, and glial reactivity, leading to changes in neuronal function and finally ischemia, edema, and hemorrhages. Current treatments are invasive and mostly applied at advanced stages, stressing the need for alternatives. To this end, we tested two unconventional and potentially complementary non-invasive treatment options: Photobiomodulation, the stimulation with near-infrared light, has shown promising results in ameliorating retinal pathologies and insults in several studies but remains controversial. Boldine, on the other hand, is a potent natural antioxidant and potentially useful to prevent free radical-induced oxidative stress. To establish a baseline, we first evaluated the effects of diabetic conditions on the retina with immunofluorescence, histological, and ultrastructural analysis in two diabetes model systems, obese LepR^db/db mice and organotypic retinal explants, and then tested the potential benefits of photobiomodulation and boldine treatment in vitro on retinal explants subjected to high glucose concentrations, mimicking diabetic conditions. Our results suggest that the principal subcellular structures affected by these conditions were mitochondria in the inner segment of photoreceptors, which displayed morphological changes in both model systems. In retinal explants, lactate metabolism, assayed as an indicator of mitochondrial function, was altered, and decreased photoreceptor viability was observed, presumably as a consequence of increased oxidative-nitrosative stress. The latter was reduced by boldine treatment in vitro, while photobiomodulation improved mitochondrial metabolism but was insufficient to prevent retinal structural damage caused by high glucose. These results warrant further research into alternative and complementary treatment options for diabetic retinopathy. Full article

(This article belongs to the Special Issue Retinal Degenerative Diseases)

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14 pages, 3684 KiB

Open AccessArticle

Dysregulation of Resolvin E1 Metabolism and Signaling in a Light-Damage Model of Age-Related Macular Degeneration

by Annamaria Tisi, Giulia Carozza, Alessandro Leuti, Rita Maccarone and Mauro Maccarrone

Int. J. Mol. Sci. 2023, 24(7), 6749; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076749 - 04 Apr 2023

Cited by 2 | Viewed by 1278

Abstract

Resolvin E1 (RvE1) is an eicosapentaenoic acid-derived lipid mediator involved in the resolution of inflammation. Here, we investigated whether RvE1 alterations may occur in an animal model of age-related macular degeneration (AMD). To this end, Sprague Dawley albino rats underwent light damage (LD), and retinas and serum were analyzed immediately or seven days after treatment. Western blot of retinas showed that the RvE1 receptor ChemR23 and the RvE1 metabolic enzymes 5-LOX and COX-2 were unchanged immediately after LD, but they were significantly up-regulated seven days later. Instead, the RvE1 receptor BLT1 was not modulated by LD, and neither was the RvE1 degradative enzyme 15-PGDH. Moreover, ChemR23, 5-LOX, COX-2 and BLT1 were found to be more expressed in the inner retina under all experimental conditions, as observed through ImageJ plot profile analysis. Of note, amacrine cells highly expressed BLT1, while ChemR23 was highly expressed in the activated microglia of the outer retina. ELISA assays also showed that LD rats displayed significantly higher circulating levels and reduced retinal levels of RvE1 compared to controls. Altogether, our data indicate that RvE1 metabolism and signaling are modulated in the LD model, suggesting a potentially relevant role of this pathway in AMD. Full article

(This article belongs to the Special Issue Retinal Degenerative Diseases)

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14 pages, 3241 KiB

Open AccessArticle

RPE-Directed Gene Therapy Improves Mitochondrial Function in Murine Dry AMD Models

by Sophia Millington-Ward, Naomi Chadderton, Laura K. Finnegan, Iris J. M. Post, Matthew Carrigan, Rachel Nixon, Marian M. Humphries, Pete Humphries, Paul F. Kenna, Arpad Palfi and G. Jane Farrar

Int. J. Mol. Sci. 2023, 24(4), 3847; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043847 - 14 Feb 2023

Cited by 2 | Viewed by 1895

Abstract

Age-related macular degeneration (AMD) is the most common cause of blindness in the aged population. However, to date there is no effective treatment for the dry form of the disease, representing 85–90% of cases. AMD is an immensely complex disease which affects, amongst others, both retinal pigment epithelium (RPE) and photoreceptor cells and leads to the progressive loss of central vision. Mitochondrial dysfunction in both RPE and photoreceptor cells is emerging as a key player in the disease. There are indications that during disease progression, the RPE is first impaired and RPE dysfunction in turn leads to subsequent photoreceptor cell degeneration; however, the exact sequence of events has not as yet been fully determined. We recently showed that AAV delivery of an optimised NADH-ubiquinone oxidoreductase (NDI1) gene, a nuclear-encoded complex 1 equivalent from S. cerevisiae, expressed from a general promoter, provided robust benefit in a variety of murine and cellular models of dry AMD; this was the first study employing a gene therapy to directly boost mitochondrial function, providing functional benefit in vivo. However, use of a restricted RPE-specific promoter to drive expression of the gene therapy enables exploration of the optimal target retinal cell type for dry AMD therapies. Furthermore, such restricted transgene expression could reduce potential off-target effects, possibly improving the safety profile of the therapy. Therefore, in the current study, we interrogate whether expression of the gene therapy from the RPE-specific promoter, Vitelliform macular dystrophy 2 (VMD2), might be sufficient to rescue dry AMD models. Full article

(This article belongs to the Special Issue Retinal Degenerative Diseases)

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19 pages, 4483 KiB

Open AccessArticle

High-Efficiency CRISPR/Cas9-Mediated Correction of a Homozygous Mutation in Achromatopsia-Patient-Derived iPSCs

by Laura Siles, Paula Gaudó and Esther Pomares

Int. J. Mol. Sci. 2023, 24(4), 3655; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043655 - 11 Feb 2023

Cited by 2 | Viewed by 2759

Abstract

Achromatopsia is an autosomal recessive disorder, in which cone photoreceptors undergo progressive degeneration, causing color blindness and poor visual acuity, among other significant eye affectations. It belongs to a group of inherited retinal dystrophies that currently have no treatment. Although functional improvements have been reported in several ongoing gene therapy studies, more efforts and research should be carried out to enhance their clinical application. In recent years, genome editing has arisen as one of the most promising tools for personalized medicine. In this study, we aimed to correct a homozygous PDE6C pathogenic variant in hiPSCs derived from a patient affected by achromatopsia through CRISPR/Cas9 and TALENs technologies. Here, we demonstrate high efficiency in gene editing by CRISPR/Cas9 but not with TALENs approximation. Despite a few of the edited clones displaying heterozygous on-target defects, the proportion of corrected clones with a potentially restored wild-type PDE6C protein was more than half of the total clones analyzed. In addition, none of them presented off-target aberrations. These results significantly contribute to advances in single-nucleotide gene editing and the development of future strategies for the treatment of achromatopsia. Full article

(This article belongs to the Special Issue Retinal Degenerative Diseases)

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10 pages, 407 KiB

Open AccessArticle

Long-Term Visual Prognosis of Patients Following Lens-Sparing Vitrectomy for Stage 4A Retinopathy of Prematurity

by Chiharu Iwahashi, Tomoki Kurihara, Kazuki Kuniyoshi and Shunji Kusaka

Int. J. Mol. Sci. 2023, 24(3), 2416; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032416 - 26 Jan 2023

Cited by 1 | Viewed by 1282

Abstract

This study evaluated the long-term visual outcomes of patients in whom at least one eye underwent successful lens-sparing vitrectomy (LSV) for stage 4A retinopathy of prematurity (ROP). A retrospective chart review was conducted using the data of 61 eyes of 42 patients with a minimum 4-year follow-up after successful LSV, with or without anti-vascular endothelial growth factor (VEGF) therapy, and whose best-corrected visual acuity (BCVA) was measurable using Landolt rings at the final visit. The mean age at the final follow-up was 10.1 ± 3.3 years. Before LSV, all eyes underwent laser ablation therapy. Twenty eyes (32.8%) with high vascular activity received anti-VEGF therapy before LSV. The mean decimal BCVA at the final follow-up was 0.23 ± 0.26 (range: hand motion to 1.2). Twenty-three eyes (54.1%) had a decimal BCVA of ≥0.4. Among 49 phakic eyes at the final examination, the mean refractive error was −10.1 ± 5.0 D, with 37 eyes (75.5%) having high myopia (>−6.0 D). No significant differences were observed in terms of decimal BCVA and refractive errors between eyes with and without anti-VEGF therapy. Approximately half of the patients had a decimal BCVA of ≥0.4, despite myopic refraction after successful LSV for stage 4A ROP. LSV for stage 4A ROP seemed to be associated with good visual function, despite myopic refraction. Full article

(This article belongs to the Special Issue Retinal Degenerative Diseases)

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17 pages, 12555 KiB

Open AccessArticle

Deletion of POMT2 in Zebrafish Causes Degeneration of Photoreceptors

by Yu Liu, Jaclyn M. Rittershaus, Miao Yu, Rachel Sager and Huaiyu Hu

Int. J. Mol. Sci. 2022, 23(23), 14809; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314809 - 26 Nov 2022

Cited by 2 | Viewed by 1696

Abstract

Mutations in the extracellular matrix protein eyes shut homolog (EYS) are a common cause of retinitis pigmentosa, a blinding disease characterized by photoreceptor degeneration. EYS binds to matriglycan, a carbohydrate modification on O-mannosyl glycan substitutions of the cell-surface glycoprotein α-dystroglycan. Patients with mutations in enzymes required for the biosynthesis of matriglycan exhibit syndromic retinal atrophy, along with brain malformations and congenital muscular dystrophy. Protein O-mannosyltransferase 2 (POMT2) is an enzyme required for the synthesis of O-mannosyl glycans. To evaluate the roles of O-mannosyl glycans in photoreceptor health, we generated protein O-mannosyltransferase 2 (pomt2) mutant zebrafish by CRISPR. pomt2 mutation resulted in a loss of matriglycan and abolished binding of EYS protein to α-dystroglycan. Mutant zebrafish presented with hydrocephalus and hypoplasia of the cerebellum, as well as muscular dystrophy. EYS protein was enriched near photoreceptor connecting cilia in the wild-type, but its presence and proper localization was significantly reduced in mutant animals. The mutant retina exhibited mis-localization of opsins and increased apoptosis in both rod and cone photoreceptors. Immunofluorescence intensity of G protein subunit alpha transducin 2 (GNAT2) antibody (a general cone marker) and 1D4 antibody (a long double cone marker) in mutant retinas did not differ from wild-type retinas at 1-month post fertilization, but was reduced at 6 months post fertilization, indicating significant cone degeneration. These data suggest that POMT2-mediated O-mannosyl glycosylation is required for EYS protein localization to the connecting cilium region and photoreceptor survival. Full article

(This article belongs to the Special Issue Retinal Degenerative Diseases)

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18 pages, 6438 KiB

Open AccessArticle

Aberrant Retinal Pigment Epithelial Cells Derived from Induced Pluripotent Stem Cells of a Retinitis Pigmentosa Patient with the PRPF6 Mutation

by Yuqin Liang, Feng Tan, Xihao Sun, Zekai Cui, Jianing Gu, Shengru Mao, Hon Fai Chan, Shibo Tang and Jiansu Chen

Int. J. Mol. Sci. 2022, 23(16), 9049; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169049 - 12 Aug 2022

Cited by 4 | Viewed by 2388

Abstract

Pre-mRNA processing factors (PRPFs) are vital components of the spliceosome and are involved in the physiological process necessary for pre-mRNA splicing to mature mRNA. As an important member, PRPF6 mutation resulting in autosomal dominant retinitis pigmentosa (adRP) is not common. Recently, we reported the establishment of an induced pluripotent stem cells (iPSCs; CSUASOi004-A) model by reprogramming the peripheral blood mononuclear cells of a PRPF6-related adRP patient, which could recapitulate a consistent disease-specific genotype. In this study, a disease model of retinal pigment epithelial (RPE) cells was generated from the iPSCs of this patient to further investigate the underlying molecular and pathological mechanisms. The results showed the irregular morphology, disorganized apical microvilli and reduced expressions of RPE-specific genes in the patient’s iPSC-derived RPE cells. In addition, RPE cells carrying the PRPF6 mutation displayed a decrease in the phagocytosis of fluorescein isothiocyanate-labeled photoreceptor outer segments and exhibited impaired cell polarity and barrier function. This study will benefit the understanding of PRPF6-related RPE cells and future cell therapy. Full article

(This article belongs to the Special Issue Retinal Degenerative Diseases)

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15 pages, 4997 KiB

Open AccessArticle

Repair of Retinal Degeneration by Human Amniotic Epithelial Stem Cell–Derived Photoreceptor–like Cells

by Jinying Li, Chen Qiu, Jiayi Zhou, Yang Wei, Weixin Yuan, Jia Liu, Wenyu Cui, Jianan Huang, Cong Qiu, Lihe Guo, Luyang Yu and Zhen Ge

Int. J. Mol. Sci. 2022, 23(15), 8722; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158722 - 05 Aug 2022

Cited by 3 | Viewed by 1640

Abstract

The loss of photoreceptors is a major event of retinal degeneration that accounts for most cases of untreatable blindness globally. To date, there are no efficient therapeutic approaches to treat this condition. In the present study, we aimed to investigate whether human amniotic epithelial stem cells (hAESCs) could serve as a novel seed cell source of photoreceptors for therapy. Here, a two–step treatment with combined Wnt, Nodal, and BMP inhibitors, followed by another cocktail of retinoic acid, taurine, and noggin induced photoreceptor–like cell differentiation of hAESCs. The differentiated cells demonstrated the morphology and signature marker expression of native photoreceptor cells and, intriguingly, bore very low levels of major histocompatibility complex (MHC) class II molecules and a high level of non–classical MHC class I molecule HLA–G. Importantly, subretinal transplantation of the hAESCs–derived PR–like cells leads to partial restoration of visual function and retinal structure in Royal College of Surgeon (RCS) rats, the classic preclinical model of retinal degeneration. Together, our results reveal hAESCs as a potential source of functional photoreceptor cells; the hAESCs–derived photoreceptor–like cells could be a promising cell–replacement candidate for therapy of retinal degeneration diseases. Full article

(This article belongs to the Special Issue Retinal Degenerative Diseases)

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Review

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17 pages, 1913 KiB

Open AccessReview

Optogenetic Therapy for Visual Restoration

by Daiki Sakai, Hiroshi Tomita and Akiko Maeda

Int. J. Mol. Sci. 2022, 23(23), 15041; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315041 - 30 Nov 2022

Cited by 14 | Viewed by 3534

Abstract

Optogenetics is a recent breakthrough in neuroscience, and one of the most promising applications is the treatment of retinal degenerative diseases. Multiple clinical trials are currently ongoing, less than a decade after the first attempt at visual restoration using optogenetics. Optogenetic therapy has great value in providing hope for visual restoration in late-stage retinal degeneration, regardless of the genotype. This alternative gene therapy consists of multiple elements including the choice of target retinal cells, optogenetic tools, and gene delivery systems. Currently, there are various options for each element, all of which have been developed as a product of technological success. In particular, the performance of optogenetic tools in terms of light and wavelength sensitivity have been improved by engineering microbial opsins and applying human opsins. To provide better post-treatment vision, the optimal choice of optogenetic tools and effective gene delivery to retinal cells is necessary. In this review, we provide an overview of the advancements in optogenetic therapy for visual restoration, focusing on available options for optogenetic tools and gene delivery methods. Full article

(This article belongs to the Special Issue Retinal Degenerative Diseases)

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